Throughout this application various publications are referred to in parenthesis. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
Decline in insulin action is a metabolic feature of aging and may be involved in the development of age related diseases including Type 2 Diabetes Mellitus (DM2) and Alzheimer's disease (AD) (Craft, 2005). Insulin-like growth factor-1 (IGF-1) is a key mediator of somatic growth and plays an important role in cell proliferation, survival and differentiation throughout life. In addition to effects on growth and development, IGF-1 plays a role in regulation of glucose metabolism. Administration of IGF-1 increases glucose uptake and inhibits hepatic glucose production in normal subjects, in insulin resistance states and in both type 1 and type 2 diabetes (Sherwin et al., 1994; Carroll et al., 2000; Simpson et al., 2004); this effect can be replicated in isolated rat muscle cells in vitro (Maher et al., 1989; Bilan et al., 1992), but not on hepatocytes with physiological IGF-1 levels (Binoux, 1995). Epidemiological studies have shown that individuals with low serum IGF-1 have a two-fold increased risk of developing glucose intolerance or DM2 (Sandhu et al., 2002). The effects of IGF-1 on insulin sensitivity are, in part, related to its ability to suppress growth hormone (GH), which has an insulin antagonistic effect; however, IGF-1 further improved insulin sensitivity when given in addition to a GH antagonist (pegvisomant), suggesting an independent enhancing effect of IGF on insulin sensitivity (O′Connell and Clemmons, 2002). Though several studies have shown an effect of IGF-1 on hepatic insulin action, the paucity of IGF-1 receptors in the hepatocytes (Frick et al., 2000) raises the question regarding how these effects are mediated.
Humanin (HN) is a recently identified peptide with a role in neuro-protection against Alzheimer's disease (AD) associated insults (Hashimoto et al., 2001). In fact, humanin was first identified from cDNA library of surviving neurons from an AD patient. Since then, its protective role has been described not only from various AD related insults, but also against prion-induced (Sponne et al., 2004) and chemical-induced damage (Mamiya and Ukai, 2001), thus broadening its role as a neuroprotective factor. Subsequently it has been shown to be protective against many other cytotoxic agents (Kariya et al., 2003) and also protect non-neuronal cells such as smooth muscle cells (Jung and Van Nostrand, 2003), rat pheochromocytoma cells (Kariya et al., 2002) and lymphocytes (Kariya et al., 2003).
Structurally, HN is a 24 amino acid polypeptide that is transcribed from an open reading frame within the mitochondrial 16S ribosomal RNA in mammals (Hashimoto et al., 2001). HN is both an intracellular and secreted protein. It has been detected in normal mouse testis and colon (by immunoblot and immunohistochemical analyses using specific antibodies against HN peptide) (Tajima et al., 2002) and is present in cerebrospinal fluid (CSF), seminal fluid and serum; levels in CSF are few orders of magnitude higher than that in circulation (P. Cohen, unpublished data). So far, little has been discovered about the regulation of its production. HN promotes cell survival by binding to a variety of pro-apoptotic protein partners, such as Bax-related proteins (Guo et al., 2003), putative cell-surface receptors (Ying et al., 2004), and IGF binding protein-3 (IGFBP-3) (Ikonen et al., 2003). IGFBP-3 is one of a number of peptides including insulin, leptin, adiponectin, and resistin that have been shown to act in the central nervous system to regulate glucose metabolism (Muse et al., 2007, Obici et al., 2002). Unlike these aforementioned peptides IGFBP-3 is an HN partner that has pro-diabetogenic hypothalamic actions that are modulated by IGF-1 (Muzumdar et al., 2006). cDNAs identical or similar to HN have since been identified in plants, nematodes, rats, mice and many other species demonstrating that it is highly conserved along evolution (Guo et al., 2003).